Some of the greatest challenges in medicine are the neurodegenerative diseases (NDs), which remain without a cure and mostly progress to death. A companion study employed a toolkit methodology to document 2001 plant species with ethnomedicinal uses for alleviating pathologies relevant to NDs, focusing on its relevance to Alzheimer\'s disease (AD). This study aimed to find plants with therapeutic bioactivities for a range of NDs. 1339 of the 2001 plant species were found to have a bioactivity from the literature of therapeutic relevance to NDs such as Parkinson\'s disease, Huntington\'s disease, AD, motor neurone diseases, multiple sclerosis, prion diseases, Neimann-Pick disease, glaucoma, Friedreich\'s ataxia and Batten disease. 43 types of bioactivities were found, such as reducing protein misfolding, neuroinflammation, oxidative stress and cell death, and promoting neurogenesis, mitochondrial biogenesis, autophagy, longevity, and anti-microbial activity. Ethno-led plant selection was more effective than random selection of plant species. Our findings indicate that ethnomedicinal plants provide a large resource of ND therapeutic potential. The extensive range of bioactivities validate the usefulness of the toolkit methodology in the mining of this data. We found that a number of the documented plants are able to modulate molecular mechanisms underlying various key ND pathologies, revealing a promising and even profound capacity to halt and reverse the processes of neurodegeneration.

UNASSIGNED: Amyotrophic lateral sclerosis is a neurodegenerative disease with wide variation of genetics associated with it. Among the different genes described, mutation in TFG is a rare finding in amyotrophic lateral sclerosis.
UNASSIGNED: A 35 years old right-handed male presenting with ipsilateral weakness was diagnosed with amyotrophic lateral sclerosis. He was found to have missense variant of TFG with uncertain significance on exome sequencing.
UNASSIGNED: The genetics involved in amyotrophic lateral sclerosis is ever-evolving. The identification of new TFG variant in this disease adds another evidence to the role of TFG in neurodegenerative disease.
UNASSIGNED: The finding of TFG variant of uncertain significance is a rare finding in amyotrophic lateral sclerosis. And with the identification of new TFG variant, it leads to further understanding of spectrum of TFG and its pathophysiology in amyotrophic lateral sclerosis.

Since the 1990s, Veterans Health Administration (VHA) has maintained a registry of Veterans with Spinal Cord Injuries and Disorders (SCI/Ds) to guide clinical care, policy, and research. Historically, methods for collecting and recording data for the VHA SCI/D Registry (VSR) have required significant time, cost, and staffing to maintain, were susceptible to missing data, and caused delays in aggregation and reporting. Each subsequent data collection method was aimed at improving these issues over the last several decades. This paper describes the development and validation of a case-finding and data-capture algorithm that uses primary clinical data, including diagnoses and utilization across 9 million VHA electronic medical records, to create a comprehensive registry of living and deceased Veterans seen for SCI/D services since 2012. A multi-step process was used to develop and validate a computer algorithm to create a comprehensive registry of Veterans with SCI/D whose records are maintained in the enterprise wide VHA Corporate Data Warehouse. Chart reviews and validity checks were used to validate the accuracy of cases that were identified using the new algorithm. An initial cohort of 28,202 living and deceased Veterans with SCI/D who were enrolled in VHA care from 10/1/2012 through 9/30/2017 was validated. Tables, reports, and charts using VSR data were developed to provide operational tools to study, predict, and improve targeted management and care for Veterans with SCI/Ds. The modernized VSR includes data on diagnoses, qualifying fiscal year, recent utilization, demographics, injury, and impairment for 38,022 Veterans as of 11/2/2022. This establishes the VSR as one of the largest ongoing longitudinal SCI/D datasets in North America and provides operational reports for VHA population health management and evidence-based rehabilitation. The VSR also comprises one of the only registries for individuals with non-traumatic SCI/Ds and holds potential to advance research and treatment for multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and other motor neuron disorders with spinal cord involvement. Selected trends in VSR data indicate possible differences in the future lifelong care needs of Veterans with SCI/Ds. Future collaborative research using the VSR offers opportunities to contribute to knowledge and improve health care for people living with SCI/Ds.

UNASSIGNED: Using transcranial magnetic stimulation (TMS) to delineate upper motor neuron (UMN) signs of two neurodegenerative disorders: amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA).
UNASSIGNED: Medical records including clinical signs for UMN damage and TMS results were reviewed retrospectively. The UMN signs were classified into none, mild, and severe based on neurological examination of various reflexes. Then TMS-elicited motor evoked potentials (MEPs) were recorded from a hand and a leg muscle to calculate the central motor conduction time (CMCT), which represents fast, mono-synaptic conduction along the corticospinal tract. Relations between the UMN signs and CMCT were analysed for the two diseases.
UNASSIGNED: Prevalence and severity of the UMN signs for ALS and MSA were comparable for both upper and lower limbs. However, abnormality in CMCT was found more frequently in ALS: CMCT abnormalities were found in upper limbs for 44% in ALS patients but only for 7% in MSA patients; CMCT abnormalities in lower limbs were 55% in ALS and 20% in MSA. Some ALS patients showed abnormal CMCT in limbs without UMN signs, which was not true for most MSA patients.
UNASSIGNED: The abnormalities of CMCT were different in ALS and MSA, even for those who clinically had similar UMN signs. Sometimes, CMCT can reveal UMN damage in the absence of clinical UMN signs. Differences presumably derive from selective degeneration of different fibres in the motor descending pathways. Longitudinal studies must be conducted to accumulate neuroimaging and pathological findings.
UNASSIGNED: CMCT can be useful to differentiate ALS and MSA.

Telomere length (TL) is a biomarker of biological aging. Shorter telomeres have been associated with mortality and increased rates of age-related diseases. However, observational studies are unable to conclude whether TL is causally associated with those outcomes. Mendelian randomization (MR) was developed for assessing causality using genetic variants in epidemiological research. The objective of this study was to test the potential causal role of TL in neurodegenerative disorders and life expectancy through MR analysis. Summary level data were extracted from the most recent genome-wide association studies for TL, Alzheimer\'s disease (AD), Parkinson\'s disease, Frontotemporal dementia, Amyotrophic Lateral Sclerosis, Progressive Supranuclear Palsy and life expectancy. MR estimates revealed that longer telomeres inferred a protective effect on risk of AD (OR = 0.964; adjusted p-value = 0.039). Moreover, longer telomeres were significantly associated with increased life expectancy (βIVW  = 0.011; adjusted p-value = 0.039). Sensitivity analyses suggested evidence for directional pleiotropy in AD analyses. Our results showed that genetically predicted longer TL may increase life expectancy and play a protective causal effect on AD. We did not observe significant causal relationships between longer TL and other neurodegenerative diseases. This suggests that the involvement of TL on specific biological mechanisms might differ between AD and life expectancy, with respect to that in other neurodegenerative diseases. Moreover, the presence of pleiotropy may reflect the complex interplay between TL homeostasis and AD pathophysiology. Further observational studies are needed to confirm these results.

When the ability to cough is impaired, secretion clearance may be assisted and augmented by Mechanical Insufflation-Exsufflation (MI-E) treatment. In patients with Amyotrophic Lateral Sclerosis, the efficacy of MI-E may be hampered by counterproductive upper airway responses. Careful adjustment of MI-E settings can be beneficial. During the disease progression, a 41-year-old woman with bulbar Amyotrophic Lateral Sclerosis experienced that treatment with MI-E was exhausting and inefficient. Despite adjustments of settings, all treatment led to retching. A change of MI-E device led to more effective treatment. A bench test revealed variations in flow and pressure waveforms in the two devices. When MI-E treatment fails, differences in equipment delivery need to be considered in addition to the adjustment of MI-E settings.

OBJECTIVE: The partial volume effect (PVE) complicates PET studies of neurodegenerative diseases, since a decreased 18F-FDG retention might be influenced by atrophy-related changes of cortical regions. Multiple partial volume correction (PVC) methods have been therefore developed, but their application in amyotrophic lateral sclerosis (ALS) is still rare. Additionally, even if metabolic changes have been established in ALS, no study yet has investigated how these may be influenced by aging and disease course. The aim of the present study was therefore to apply and compare multiple PVC approaches to explore aging and disease course-related hypometabolism in ALS.
METHODS: PET and MRI data from 15 ALS patients were analyzed using PETSurfer to implement 4 distinct PVC methods: noPVC, Meltzer (MZ), Müller-Gärtner (MG) and Symmetric Geometric Transfer Matrix (SGTM). For each method and Region of Interest (ROI), the 18F-FDG value was regressed against subject age and disease duration.
RESULTS: MG/SGTM application almost halved the number of regions showing a significant age-related hypometabolism, while the same effect was not observed for disease course, where only the distribution of identified regions varied. Three distinct patterns emerged: regions showing a significant age/disease course-related effect across all the different methods, regions yielding significance only with MG/SGTM application, and regions maintaining significance only with noPVC/MZ application.
CONCLUSIONS: Significant changes in the distribution of aging and disease course-related hypometabolism were observed when the effect of the underlying structural status was considered, supporting the need for investigate the impact of PVE on PET-assessed metabolic changes in clinical and research settings.

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease, progressive nature characterizes by loss of both upper and lower motor neuron functions. One of the major challenge is to understand the mechanism of ALS multifactorial nature. We aimed to explore some key genes related to ALS through bioinformatics methods for its therapeutic intervention. Here, we applied a systems biology approach involving experimentally validated 148 ALS-associated proteins and construct ALS protein-protein interaction network (ALS-PPIN). The network was further statistically analysed and identified bottleneck-hubs. The network is also subjected to identify modules which could have similar functions. The interaction between the modules and bottleneck-hubs provides the functional regulatory role of the ALS mechanism. The ALS-PPIN demonstrated a hierarchical scale-free nature. We identified 17 bottleneck-hubs, in which CDC5L, SNW1, TP53, SOD1, and VCP were the high degree nodes (hubs) in ALS-PPIN. CDC5L was found to control highly cluster modules and play a vital role in the stability of the overall network followed by SNW1, TP53, SOD1, and VCP. HSPA5 and HSPA8 acting as a common connector for CDC5L and TP53 bottleneck-hubs. The functional and disease association analysis showed ALS has a strong correlation with mRNA processing, protein deubiquitination, and neoplasms, nervous system, immune system disease classes. In the future, biochemical investigation of the observed bottleneck-hubs and their interacting partners could provide a further understanding of their role in the pathophysiology of ALS.

Transactive response DNA-binding protein 43 kDa (TDP-43) is a highly conserved and widely expressed protein in human tissues that regulates nucleic acid processing. In frontotemporal dementia and amyotrophic lateral sclerosis, however, TDP-43 forms insoluble aggregates in central nervous tissues. These pathological deposits of TDP-43 have been primarily studied by ligand binding, namely western blot analysis, and, thus, methods with greater structural resolution are needed to aid in our understanding of the pathological processes associated with TDP-43 misfolding and aggregation. Toward this goal, we have developed a selective and multiplex method for the detection and characterization of TDP-43 using liquid chromatography tandem mass spectrometry. As proof-of-concept, the method was applied to the detection and characterization of TDP-43 in human cell lines and human brain tissue.

A few patients with Hashimoto\'s thyroiditis or Graves\' disease develop a multiform syndrome of the central nervous system (CNS) termed Hashimoto\'s encephalopathy or steroid-responsive encephalopathy associated with autoimmune thyroid disease (HE/SREAT). They have high levels of thyroid autoantibodies (TgAb, TPOAb and/or TSH-R-Ab) in blood and cerebrospinal fluid. Autoantibodies against alpha-enolase, aldehyde reductase-I (AKRIA) and/or dimethylargininase-I (DDAHI), proteins expressed in the CNS among other tissues, were detected in the blood and, when searched, in the cerebrospinal fluid of HE/SREAT patients. Recently, we reported that alpha-enolase, AKRIA and DDAHI share local sequence homology with each of the three autoantigens (TgAb, TPOAb, TSH-R-Ab), often in epitope-containing segments of the thyroid autoantigens. We hypothesized that there might be additional CNS-expressed proteins homologous to thyroid autoantigens, possibly overlapping known epitopes of the thyroid autoantigens. We used bioinformatic methods to address this hypothesis. Six, 27 and 47 of 46,809 CNS-expressed proteins share homology with TSH-R, Tg and TPO, respectively. The homologous regions often contain epitopes, and some match regions of thyroid autoantigens which have homology with alpha-enolase, AKRIA and/or DDAHI. Several of the aforementioned proteins are present in CNS areas that show abnormalities at neuroimaging in HE/SREAT patients. Furthermore, autoantibodies against some of the said six, 27 and 47 proteins were reported to be associated with a number of autoimmune diseases. Not only we validated our hypothesis, but we think that such a variety of potential CNS targets for thyroid Ab against epitopes contained in regions that have local homology with CNS proteins may explain the polymorphic phenotypes of HE/SREAT. Only when elevated amounts of these Ab are synthesized and trespass the blood-brain barrier, HE/SREAT appears. This might explain why HE/SREAT is so relatively rare.